rs17355446

Variant names:

• chr2-178724514-G-A
• rs17355446
• NM_001267550.2:c.20861C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.20861C>T​(p.Ala6954Val) variant causes a missense change. The variant allele was found at a frequency of 0.0317 in 1,600,914 control chromosomes in the GnomAD database, including 2,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (245 hom., cov: 33)
  • Exomes 𝑓: 0.032 (1883 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 6.55
• Publications: 14 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

ENSG00000267784 (HGNC:):

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015490651).
• BP6: Variant 2-178724514-G-A is Benign according to our data. Variant chr2-178724514-G-A is described in ClinVar as Benign. ClinVar VariationId is 46677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.20861C>T	p.Ala6954Val	missense_variant	Exon 72 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.20861C>T	p.Ala6954Val	missense_variant	Exon 72 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4950 AN: 152002 Hom.: 241 Cov.: 33

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0567

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0568 AC: 13832 AN: 243530 AF XY: 0.0555

Gnomad AFR exome AF: 0.00584

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.000729

Gnomad FIN exome AF: 0.0555

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0470

GnomAD4 exome AF: 0.0316 AC: 45745 AN: 1448794 Hom.: 1883 Cov.: 33 AF XY: 0.0335 AC XY: 24086 AN XY: 718336

African (AFR) AF: 0.00509 AC: 168 AN: 33030

American (AMR) AF: 0.180 AC: 7890 AN: 43916

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 497 AN: 25734

East Asian (EAS) AF: 0.000508 AC: 20 AN: 39376

South Asian (SAS) AF: 0.121 AC: 10283 AN: 85186

European-Finnish (FIN) AF: 0.0566 AC: 3007 AN: 53112

Middle Eastern (MID) AF: 0.0374 AC: 213 AN: 5692

European-Non Finnish (NFE) AF: 0.0197 AC: 21752 AN: 1103008

Other (OTH) AF: 0.0321 AC: 1915 AN: 59740

GnomAD4 genome AF: 0.0326 AC: 4958 AN: 152120 Hom.: 245 Cov.: 33 AF XY: 0.0385 AC XY: 2864 AN XY: 74346

African (AFR) AF: 0.00657 AC: 273 AN: 41536

American (AMR) AF: 0.131 AC: 1996 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3468

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5148

South Asian (SAS) AF: 0.125 AC: 600 AN: 4814

European-Finnish (FIN) AF: 0.0567 AC: 601 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0194 AC: 1318 AN: 67976

Other (OTH) AF: 0.0284 AC: 60 AN: 2110

Alfa AF: 0.0224 Hom.: 295

Bravo AF: 0.0340

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0195 AC: 75

ESP6500AA AF: 0.00710 AC: 28

ESP6500EA AF: 0.0190 AC: 158

ExAC AF: 0.0498 AC: 6026

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0180

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.17129C>T (p.Ala5710Val) results in a non-conservative amino acid change located in the I-band of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.057 in 243530 control chromosomes, predominantly at a frequency of 0.18 within the Latino subpopulation in the gnomAD database, including 584 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 288-folds over the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. A ClinVar submission (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 12, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes an amino acid but is considered to be benign based on its h igh population frequency (>3%). -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Tibial muscular dystrophy Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1G Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype Benign:1

Nov 16, 2012

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;.;T
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-1.2	T
PhyloP100		6.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.55	T;.;.;.
Polyphen		0.81	.;.;P;P
Vest4		0.14
MPC		0.14
ClinPred		0.016	T
GERP RS		6.0
Mutation Taster		=77/23	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17355446; hg19: chr2-179589241; COSMIC: COSV60305834;